Macrophage-directed strategies for BRCA-associated breast cancer

Poly (ADP-ribose) polymerase inhibitors (PARPi’s) are a promising treatment for BRCA-associated breast cancer, exerting synthetic lethal effects in homologous recombination (HR) repair-deficient tumor cells, yet clinical results are not durable. Our team has demonstrated that PARPi-mediated DNA damage in tumors also activates cGAS/STING signaling resulting in immune infiltration, including T-cells. Although these immunomodulatory effects are critical for maximal efficacy of PARPi’s, to date, the addition of PD-1/L1 blockade has not improved PARPi efficacy in preclinical models or in clinical trials. Our recent preclinical work has demonstrated that PARP inhibition also results in infiltration of CSF-1R+ tumor-associated macrophages (TAMs) that carry a highly immunosuppressive phenotype. CSF-1R blockade depletes these TAMs and significantly augments PARPi efficacy in the K14CreBrcaf/f;Tp53f/f mouse model in a CD8+ T-cell-dependent manner. Based on these data, we recently activated a Phase 1 clinical trial, AXALAP, that combines the anti-CSF-1R antibody axatilimab and olaparib in patients with PARPi-naïve or sensitive metastatic BRCA-associated breast cancer. In Aim 1, these preclinical findings will be validated in tumor biopsies procured pre-treatment, after a 2-week lead- in of olaparib alone, and after combined olaparib plus axatilimab from patients enrolled in the AXALAP clinical trial. Bulk and single cell RNA sequencing and cyclic immunofluorescence (CyCIF) will be used to deeply characterize both the T-cell and TAM components of the tumor microenvironment in response to olaparib plus axatilimab. TAM diversity before and on-treatment will be explored based on transcriptionally defined unique subsets. The topology and spatial relationships of TAMs with T-cells will also be explored. In Aim 2, we will leverage our recent discovery that CSF-1R(neg)CD40+ TAMs are maintained in murine tumors after PARPi plus anti-CSF-1R therapy and are also present in human breast tumors treated with PARPi therapy. CD40 agonists have been shown to activate TAMs and dendritic cells (DCs) to induce potent anti-tumor T cell responses in both the preclinical and clinical setting. Therefore, CD40 agonism may enhance the activity of the PARPi plus anti- CSF-1R combination. Here, we will assess the effects of PARPi + anti-CSF-1R in combination with CD40 agonism on tumor growth in long term efficacy studies and on the TME using sophisticated immunophenotyping in Brca1-deficient mouse models. In Aim 3, we will characterize DNA repair-based and immunologic mechanisms of resistance in olaparib-resistant tumors. Combined CSF-1R blockade and PARP inhibition will be studied in our preclinical immunocompetent models of Brca1-deficient breast cancer that have been trained to be PARPi-resistant. Combined PARP inhibition and CSF-1R blockade will also be studied with CD40 agonism to activate anti-tumor macrophages and DCs to overcome PARPi resistance. Taken together, these studies will define the T-cell and TAM components of the TME in response to PARP inhibition in patient samples and develop the strategy of combined CSF-1R blockade and PARP inhibition in PARPi-sensitive and resistant tumors. Project Number: 1R01CA307291-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Jennifer Guerriero (+2 co-PIs) | Institution: BRIGHAM AND WOMEN'S HOSPITAL, BOSTON, MA | Award Amount: $772,208 | Activity Code: R01 | Study Section: Clinical Oncology Study Section[CONC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11272863